3-(alpha-substituted amino-beta-alkoxybenzoxypropyl)-6,7-or 6,7,8-alkoxy-1,2,3-benzotriazine-4(3h)-ones

ABSTRACT

THE PRESENT INVENTEION PERTAINS TO NEW, PHARMACOLOGICALLY VALUABLE BASICALLY SUBSTITUTED 1,2,3-BENZOTRIAZINE-4(3H)-ONE DERIVATIVES HAVING EXCELLENT CORONARY DILATOR PROPERTIES AND WHICH HAVE THE STRUCTURAL FORMULA   3-(((R3)M-PHENYL)-COO-CH(-CH2-R&#39;&#39;)-CH2-),(R1)N-1,2,3-BENZO-   TRIAZIN-4(3H)-ONE   WHEREIN R&#39;&#39; IS A RADICAL SELECTED FROM THE GROUP CONSISTING OF N,N - DI - LOWER-ALKYLAMINO, N-LOWER-ALKYL-N-ALLYLAMINO, N-LOWER-ALKYL-N-(METHOXY-LOWER-ALKYL)-AMINO, N-LOWER-ALKYL-N-(DIETHYLAMINO-LOWER-ALKYL)-AMINO AND N-LOWER-ALKYL-N-BENZYL-AMINO,LOWER ALKYL MEANING ALKYL HAVING 1 TO 4 CARBON ATOMS, SAID RADICAL BEING BOUND VIA IS NITROGEN ATOM, R1 IS A LOIWER ALKOXY GROUP HAVING 1-4 CARBON ATOMS WHICH MAY BE IN THE 6,7 OR 6,7,8-POSITION, R2 IS AN ALKOXY GROUP HAVING 1-4 CARBON ATOMS, M IS AN INTEGER SELECTED FROM 1,2 AND 3, AND N IS AN INTEGER SELECTED FROM THE GROUP CONSISTING OF 2 AND 3 AND PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF.

United States Patent 3,751,413 3 (oz-SUBSTITUTED AMlNO-fl-ALKOXYBENZOXY-PROPYL)-6,7- OR 6,7,8-ALKOXY 1,2,3-BENZO- TRIAZINE-4(3H)-ONES AdolfStachel, deceased, by Ingeburg Lydia Katharina Stachel, heiress, 4Bierbrauerweg, 605 Offenbach (Main), Germany; Rudi Beyerle, 15Allensteinerstrasse, 6451 Bruchkobel, Germany; Rolf-Eberhard Nitz, 4Heinrich-Bingemer-Weg, 6 Bergen-Enkheim, Germany; and Klaus Resag, 15Hunfelderstrasse; and Eckhard Schraven, 24 Fuldaerstrasse, both of 6Frankfurt am Main-Fechenheim, Germany No Drawing. Original applicationMay 18, 1970, Ser. No. 38,544, now Patent No. 3,706,739. Divided andthis application June 22, 1972, Ser. No. 265,221 Claims priority,application Germany, May 22, 1969, P 19 26 075.4 Int. Cl. C07d 55/08U.S. Cl. 260-248 AS 4 Claims ABSTRACT OF THE DISCLOSURE The presentinvention pertains to new, pharmacologically valuable basicallysubstituted 1,2,3-benzotriazine-4(3H)-one derivatives having excellentcoronary dilator properties and which have the structural formula EfIF-CHPC H-CHa-R wherein R is a radical selected from the groupconsisting of N,N di lower-alkylamino, N-lower-alkyl-N-allylamino, Nlower-alkyl-N-(methoxy-lower-alkyl)-amino,N-lower-alkyl-N-(diethylamino-lower-alkyl)-amino andN-lower-alkyl-N-benzyl-amino, lower alkyl meaning alkyl having 1 to 4carbon atoms, said radical being bound via its nitrogen atom; R is alower alkoxy group having 1-4 carbon atoms which may be in the 6,7 or6,7,8-position; R is an alkoxy group having 1-4 carbon atoms; In is aninteger selected from 1, 2 and 3; and n is an integer selected from thegroup consisting of 2 and 3 and pharmaceutically acceptable acidaddition salts thereof.

IFF-CHrCHF-CH R' wherein R is a radical selected from the groupconsisting of a secondary aliphatic, cycloaliphatic, araliphatic amineice having 2 to 10 carbon atoms or of a 5, 6 or 7-membered heterocyclicnitrogen base, which contains in the nucleus besides the nitrogen atom acorresponding number of methylene groups as well as a further nitrogenatom, an O or an S atom, said radical being bound via a nitrogen atom,

R stands for lower alkoxy groups having 1 to 4 carbon atoms which may bein the 6,7 or 6,7,8-position,

R represents alkoxy having 1 to 4 carbon atoms,

In: stands for the integers 1, 2 or 3 and It means the integers 2 or 3.

Furthermore, the present invention relates to processes for theproduction of said compounds.

The present application is a division of our United States Ser. No.38,544, filed May 18, 1970, now US. Pat. No. 3,706,739.

The radical of a secondary amine R which is bound via a nitrogen atommay derive in the aliphatic series from mono and diamines, such asdialkylamines, alky1- alkenylamines, alkylenediamines,hydroxyalkylamines and alkoxyalkylamines.

Such amines are for instance: dimethylamine, diethylamine,allylmethylamine, N,N diethyl N' methylethylenediamine, N,N diethyl Nmethylpropylenediamine, N-methylethanolamine, N-methylpropanolamine,N-isopropylethanolamine, N-butylethanolamine, N-benzylethanolamine,N-methylmethoxypropylamine, N-methylethoxypropylamine.

Cycloaliphatic amines may be for instance: N-methylcyclopropylamine,N-methylcyclohexylamine.

Amines of the araliphatic series may be for instance:phenalkylalkylamines such as benzylmethylamine, phenethylmethylamine.

Heterocyclic nitrogen bases may be for instance: 5, 6 and 7-memberedheterocyclic nitrogen bases such as pyrrolidine, morpholine,thiomorpholine, piperidine, N-methylpiperazine, N-phenylpiperazine,N-(B-hydroxyethyD- piperazine, N- y-hydroxypropyl)-piperazine,hexamethyleneimine.

The 1,2,3-benzotriazine-4(3H)-one derivatives of the present inventionare obtained by (a) Acylating, optionally in the presence of anacidbinding agent, 1,2,3-benzotriazine-4(3H)-one derivatives of thegeneral formula is NCH -CHOHz-R 1) N H fl wherein R has the above-givenmeaning, R is identical with R or, in case R contains an acyloxy radicalof the general formula said R may represent the residue of theunderlying hydroxy compound, with an alkoxy benzoic acid of the generalformula or a functional derivative thereof, or

3 4 (b) Cyclizing substituted o-aminobenzamides of the of a platinelectrode of the Gleichmann-Liibbers type general formula (see U.Gleichmann and -D. W. Luebhers Die Messung des Sauerstofidruckes inGasen und Fliissigkeiten mit der Platin-Elektrode unter besondererBeriicksichtigung der 5 Messung im Blut, Ptfliigers Arch. 271, 431-455(1960) NH-OHz-CH-CHa-R' The heart rate was continuously measured byelectronic methods from systolic peaks of the arterial blood presg sure.The arterial blood pressure was measured in the 2 f known manner in thefemoral artery with the aid of an electromanometer of theStatham-strain-gauge type.

(32), The following table gives the results of the pharmacologicalinvestigations which were carried through. The preparations were testedin the form of their respective with nitrous acid. hydrochlorides:

Maximal increase Maximal change in in oxygen tension the blood pressureLD 50, in the coronary Maximal change in (systolic/diastolic) g. Dosage,veinons blood inthe heart rate ininmuuse, nag/kg, Preparation i.v. l.v.Percent Minutes Percent Minutes Percent Minutes 3- h u 3,4,5-tri thbenzo r0 143,7 8-

thg igiiio ii zf abenzotnghino ihH)on iifiinlflnnnn 0.2 0.5 +106 25 -1925 -43/-32 25347-(4'-fi-3,4,5-trlmethoxybenzoxyethylplperazino)-B-(3,4,5-

trimethoxybenzoxy)-propyl]-fi,7,8-trlmethoxy-1,2,3-henzotriaziue-4(3H)-0.25 0.5 +109 60 5 20 -22/-3l 003-h-morpholinofi-(3,5-dimethoxybenzoxy)-propyl]-6,7,8-

trimethoxy-l,2,3-benzotriazine-4(3H)-one 025 0.5 +57 15 +23 15 -25/19 15a-h-morpholino-B-(3,5-dimeth0xy-4-n-butoxybenzoxy)-propyl]-6,7,8-trirnethoxy-l,2,3-benzotriazine-4(3H)one 0.4 0.5 +55 40 10 40-32/25 35 fl-l'y-piperidino-fi-(3,4,5-tri1neth0xybenzoxy)-propyl]fi,7,8o

trimethoxy-l,2,3-benzotriazine-4(3H)-0ne 0.1 0.5 +25 35 5 35 +0/12 153-{-y-hexamethyleneimino-B-(3,4,5-trimethoxybenzoxy) ropy6,7,8-trimethoxy-l,2,3-benzotriaZine4(3H)-0ne .4: 0.13 0.5 +19 -12 30-4/18 20 a-h-( iqnethylpiperazino-;3-(3,4,fi-trimethoxybenzoxy)-propyl}-6,7,8-trimethoxy-l,2,3-beriZotriaZine-4(3H)-0n8 0.24 2.0 +65 65 -5 65-7/l4 15 S-[y-(eV-phenylpiperazino)-B-(3,4,5-trimethoxyhenzoxy)-propyl]-6,7,8-trirnethcry-1,2,3-benzotriazlne-4(311)-0118 025 0.5 +17 15 -3 154/-6 15 3-[ -pyrro1idino-B-(3,4,5-trimethoxybenzoxy)-pr0pyl]-6,7,8-

trimethoxy-l,2,3-benzotriazine-4(3H)-one H: 0.043 0.5 +79 80 --11 80=l=0 3-['y-(N-methyl-N-v-rnethoxy propylamino)fl-(3,4,5-trimethoxybenzoxy)-propyl}-6,7,8-tri.methoxy-1,2,3-benzotriazine-4(3H)-nne 0.5 +138 210 -1a -35/30 a5 3-['y-(N-methyl-Nvdiethylaminopropylamino)-8-(3,4,5-trimethoxybeuzoxy)-pr0pyl]-6,7,8-trimeth0xy-1,2,3-benz0-triaZine-4(3H)-nne 0.028 2.0 +207 155 -15 155 -51/-4s 155 34-(N-rnethyl-N-henzylamino) --(3,4,5-trlmethoxybenzoxy)-propyl]-6,7,8-trimethoxy-1,2,3 benzotriaZine-4(3H)-0nc 0.17 0.5 +128 7021 70 27/-35 70 If, according to the process described under para (a),For a better understanding of the nature and the obinitial products areused wherein the radical of an amine jects of this invention, referenceshould be made to the R, which is bound via a nitrogen atom, contains ahyaccompanying examples which are of an illustrative droxyalkyl group,and if 2 mols of alkoxy benzoic acid rather than a limiting nature.Unless otherwise stated, or of a functional derivative thereof areemployed, one all temperatures given are in degrees centigrade. obtainsthe corresponding diesters. The 3-(y-amino49-hy- EXAMPLE 1droxypropyl)-1,2,3-benzotriazine-4(3H)-ones required as startingmaterial may be obtained by various ways of 0 preparation according tothe teachings of the correspondi ing application having the same titleand the same filing 011,0 date. I l

The initial products required for the process described SE30 A underpara (b) may be prepared in the usual manner N 0=o according to knownper se processes. The nitrous acid 06H: which causes the cyclization isformed in an acid reaction medium from the alkali metal nitritesemployed.

The 1,2,3-benzotriazine-4(3H)-one derivatives of the HiiO CH; presentinvention are valuable pharmaceuticals. In particular, they areexcellent coronary dilators and, in this re- 0H: spect superior to otherknown substances of this 3& ((11 l) 3..( c h 1i .p.h d 1)- W respect thechange 111 the y o ns m 6,7,8 trimethoxy-1,2,3-benzotriazine-4(3H)-oneare disthe coronary veinous blood, the pharmacological investisolved in250 cc. anhydrous benzene and 11.1 g. (0.11 canon t the vasodllatoraction o the coronary ss ls mol) triethylamine are added. Subsequently,a solution was carrie t i dogs aooordmg o t th ds d of 25.3 g. (0.11mole) 3,4,5-trimethoxybenzoyl chloride scribed by W. K. A. Schaper andhis coworkers (see in 100 cc. anhydrous benzene are added dropwise whileW. K. A. Schaper, Xhomlellx, and M- Bogaar stirring at room temperatureduring 30 minutes and stir- Ube dle kfllltmlllerllcho g desSauerstotfdruckcs ring is continued for 2 hours at room temperature. Theim venfisen Coronarblnt (Naunyn-schmiedebergs Arch. reaction mixture isthen stirred for another 6 hours unexp. Path. u. Pharmak 24 5, 383-389(1963)). The test der reflux and sucked off, while hot, from thetriethylpreparations were apphedmtravenously to the narcouzed aminehydrochloride being precipitated. The filtrate is and spontaneouslybreathing animals. On these test conwashed with water, with a 10%aqueous sodium bicarditions the dilatation of the coronary arteriescaused by bonate solution and again with water and finally dried thetest substances along with the increase in the coronary over anhydroussodium sulfate. Subsequently, the solvent blood flow led to an increasein the oxygen tension in is distilled off at 50 in the water-jet vacuum.The resthe coronary veinous blood. This oxygen tension was idue, acolorless crystal powder, is triturated with little measured accordingto polarographic methods by means ethyl acetate and sucked 01f. Byrecrystallization from ethyl acetate one obtains the3-[-y-morpholino-fi-'(3,4,5- trimethoxybenzoxy)propyl]-6,7,8-trimethoxy-1,2,3-benzotriazine-4(3H)-one in the form ofcolorless crystals having a melting point of 142-144". Yield: 48 g.(=84% of the theoretical).

49.6 g. (0.1 mol) 3-['y-(4'-fl-hydroxyethylpiperazino[1])-;8hydroxy-propyl]-6,7,8-trimethoxy 1,2,3 benzotriazine- 4(3H)-onedihydrochloride are dissolved in 500 cc. anhydrous chloroform with theaddition of 40.4 g. (0.4 mol) triethylamine. A solution of 46 g. (0.2mol) 3,4,5-trimethoxybenzoyl chloride in 150 cc. anhydrous chloroform isadded dropwise while stirring within 1 hour. After the decay of theexothermic reaction stirring is continued for another 2 hours at 40-50.The thusly obtained reaction mixture is first washed several times withwater, then with a 10% aqueous sodium bicarbonate solution and againwith water. Subsequently, the solvent is distilled ofi at 40 in thewater-jet vacuum and the residue, a light yellow oil, is dissolved, forfurther purification purposes,

in dilute aqueous hydrochloric acid. This solution is extracted withether and filtered in order to become limpid. By the addition ofpotassium carbonate until the reaction mixture shows an alkalinereaction (pH 9), the diester being formed separates in the form of acolorless oil. It is extracted with ethyl acetate which is washedseveral OCH:

OCH;

times with water and dried over anhydrous sodium sulfate. The solvent isthen distilled off at in the waterjet vacuum and the residue, acolorless oil, is dissolved in anhydrous ether. By the addition ofetheric hydrochloric acid until congo paper turns blue one obtains thedihydrochloride of the3-['y-(4-,8-'3,4,5-trimethoxybenzoxyethylpiperazino[1']) 13 3,4,5trimethoxybenzoxypropyl]-6,7,8-trimethoxy i1,2,3 benzotn'azine-4(3H)-onein the form of colorless crystals decomposing at 150. Yield: g. (=79% ofthe theoretical).

Analogously to the description given in Examples 1 and 2 the followingcompounds of the present invention may be prepared:

General formula:

N CHQCH CHQ RI 1) l Melting point (hydrochloride) l)n 2)m R degrees 67,8-(0 CH:)s-----.- O CH I 125 Same (|)CH5 m D0 (I) 2115 N(CzH5):200-202 O C2H D0 (|)CH3 same 208-210 -0 o-o om Do Same 190 Do d0 Meltingpoint hi ii c on e 4) (B2), R degrees! Same .d 160 -N N-CH:

Do do 163 -N N-CH5 Do (in 80 I 130...? (in CfHa 130 N--CH:CH1CHg-O-CH3 Dd0 CH3 75 N-CH:CHnCHz-N(C:Hr):

Dn o on, 75

N GHZOQHE Do do (1H 85 --NCH:CH=CH2 D" d0 (3H3 85 D n (in CH; 95

I --NCH 67-(0013'0- do I 136-138 Dn do 220 D do N(G!H): 195

D0 .dO CH 0 -N-GHPCH=CH D0 (10..----. CH; 165

-N-CH2CHzCH2-N(C3Hs):

D0 do Ban N N-GHg-CHaO O C OCH:

OCH:

1 Dihydrochloride.

EXAMPLE 3 2-nitro-3,4,5-trimethoxy-N-['y-diethylamino-B-(3,4,5-

2-nitro-3,4,5-trimethoxy-N-(y-diethylamim-B- hydroxypropyl) -benzan1ide82.6 g. (0.3 mol) 2-nitro-3, 4,5-trimethoxybenzoyl chloride aredissolved in 200 cc. anhydrous benzene and added dropwise, whilestirring, to a solution consisting of 43.8 g. (0.3 mol)'y-diethylamino-B-hydroxypropylamine and 30.3 g. (0.3 mol) triethylaminein 500 cc. anhydrous benzene. Stirring is continued for 3 hours underreflux and after cooling down, the filtrate is evaporated to dryness invacuo. For further purification purposes the crude product is dissolvedin dilute hydrochloric acid and, after filtration, the filtrate isrendered alkaline by the addition of an aqueous potassium carbonatesolution. The base which hereby separates in the form of an oil, isdissolved in ethyl acetate and washed several times with water. Afterdrying over potassium carbonate the ethyl acetate solution isconcentrated in vacuo and thus obtained is the2-nitro-3,4,S-trimethoxy-N-(y-dietliylamino-fl-hydroxypropyl)-benzamidein the form of a yellowish oil. Yield: 91 g. (=79% of the theoretical).

trimethoxybenzoxy) -propyl] -benzamide 38.5 g. (0.1 mol)2-nitro-3,4,5-trimethoxy-N-('y-diethylamino B hydroxypropyl)-benzamideand 15.15 g. (0.15 mol) triethylamine are dissolved in 200 cc. anhydrousbenzene and admixed with stirring with a solution consisting of 34.5 g.(0.15 mol) 3,4,5-trimethoxybenzoyl chloridein cc. anhydrous benzene.Subsequently, the reaction mixture is heated to the boil and stirring iscontinued for 6 hours under reflux. After cooling down the reactionproduct is stirred out with 300 cc. water and the benzene layer isseparated. Subsequently, the benzene layer is shaken out with dilutehydrochloric acid. The aqueous hydrochloric acid solution is renderedalkaline by the addition of aqueous potassium carbonate solution and thebase which separates in the form of an oil is dissolved in ethylacetate. The thnsly obtained ethyl acetate solution is washed with waterand evaporated to dryness, after drying over potassium carbonate, invacuo. For further purification the crude product is recrystallized.from alcohol.

Thus obtained is the 2-nitro-3,4,5-trimethoxy-N-[qr-diethylamino B(3,4,5 trimethoxybenzoxy)-propyl]- benzamide in the form of light yellowcrystals melting at 107. Yield: 46 g. (=79.5% of the theoretical).

2-amino-3 ,4,5 -trimethoxy-N- ['y-diethylamino- 8- 3,4,5-

trimethoxybenzoxy)-propyl]-benzamide 58 g. (0.1 mol)2-nitro-3,4,5-trimethoxy-N-['y-diethylamino B (3,4,5trimethoxybenzoxy)-propyl]-benzamide are dissolved in 250 cc. methanoland hydrogenated at 3040 in the presence of Raney nickel at a hydrogenpressure of 70 atmospheres. The reaction product is sucked off from thecatalyst and the filtrate is evaporated to dryness in vacuo. The oilyresidue is dissolved in ethyl acetate and by the addition of etherichydrochloric acid the dihydrochloride of the2-amino-3,4,5-trirnethoxy-N-['y-diethylamino B (3,4,5trimethoxybenzoxy)-propyl]-benzamide is precipitated in the form ofcolorless needles having a decomposition point of 75. Yield: 49 g.(=78.7% of the theoretical).

3-[y-diethylamino-fl-(3,4,5-trimethoxybenzoxy) -propyl]-6,7,8-trimethoxy-l,2,3-benzotriazine-4(3H)-one 31 g. (0.05 mol)2-amino-3,4,5-trimethoxy-N['y-diethylamino B (3,4,5trimethoxybenzoxy)-propyl]- benzamide dihydrochloride are dissolved in100 cc. water and at -5 admixed dropwise while stirring and cooling witha solution consisting of 3.5 g. (0.05 mol) sodium nitrite in 20 cc.water. Stirring is continued for 2 hours at 05, then the temperature isallowed to reach room temperature. After having stirred overnight, thereaction mixture is rendered neutral by the addition of aqueous sodiumbicarbonate solution and the reaction product that precipitates in theform of crystals is sucked off. For further purification purposes it isthen recrystallized from methanol. Thus obtained is the3-['y-diethylamino-fl-(3,4,5- trimethoxybenzoxy)-propyl] 6,7,8trimethoxy 1,2,3- benzotriazine-4(3H)-one in the form of colorlessneedles melting at 92-95". Yield: 22 g. =78.6% of the theoretical).

What is claimed is:

1. A compound having the structural formula wherein R is a radicalselected from the group consisting of N,N di lower-alkylarnino,N-lower-alkyl-N-allylamino, N lower alkyl N (methoxy-loWer-alkyl)-amino, N lower alkyl N (diethylamino-lower-alkyl)- amino and N loweralkyl N benzyl amino, loweralkyl meaning alkyl having 1 to 4 carbonatoms, said radical being bound via its nitrogen atom; R is a loweralkoxy group having 1-4 carbon atoms which may be in the 6, 7 or6,7,8-position; R is an alkoxy group having l-4 carbon atoms; m is aninteger selected from 1, 2 and 3; and n is an integer selected from thegroup consisting of 2 and 3 and pharmaceutically acceptable acidaddition salts thereof.

2. 3 [v (N methyl-N-y-methoxy-propylamino)13- (3,4,5-trimethoxybenzoxy)propyl] 6,7,8 trimethoxy- 1,2,3 benzotriazine 4(3H)-one andpharmaceutically acceptable acid addition salts thereof.

3. 3 [7 (N methyl N 'y-diethylaminopropylamino) 3 (3,4,5trimethoxybenzoxy)-propyl]-6,7,8- trimethoxy 1,2,3 benzotriazine4(3H)-one and pharmaceutically acceptable acid addition salts thereof.

4. 3 ['y (N methyl N benzylamino)-fl-(3,4,5- trimethoxybenzoxy) propyl]6,7,8 trimethoxy-1,2,3- benzotriazine 4( 3H) one and pharmaceuticallyacceptable acid addition salts thereof.

References Cited FOREIGN PATENTS 1,926,076 12/1970 Germany.

OTHER REFERENCES Chemical Abstracts, vol. 74, col. 53859w.

JOHN M. FORD, Primary Examiner US. Cl. X.R.

